Therapeutic agent

ABSTRACT

The use of (+)-sibutramine in the treatment of depression, obesity, Parkinson&#39;s disease, cerebral function disorders and diabetes is described.

RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional ApplicationSerial No. 60/125,320, entitled “Therapeutic Agent,” filed on Mar. 19,1999; the entire contents of which are hereby incorporated herein byreference.

BACKGROUND OF THE INVENTION

[0002] The preparation and use of compounds of formula I, such asN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine (orN-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N,N-dimethylamine)and salts thereof, in the treatment of depression is described inBritish Patent Specification 2098602. The use of compounds such asN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine andsalts thereof in the treatment of Parkinson's disease is described inEuropean Patent Number 282206. The use ofN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine andsalts thereof in the treatment of cerebral function disorders isdescribed in U.S. Pat. No. 4,939,175. The use ofN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylaminehydrochloride in the treatment of obesity is described in EuropeanPatent Number 397831. A particularly preferred form of this compound isN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylaminehydrochloride monohydrate (sibutramine hydrochloride mono-hydrate) whichis described in European Patent Number 230742. The use ofN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine andsalts thereof for improving the glucose tolerance of humans havingImpaired Glucose Tolerance or Non-Insulin Dependent Diabetes Mellitus isdescribed in published PCT application WO95/20949.

[0003] All of the above documents are incorporated herein by reference.

[0004] The use of sibutramine as an insulin sensitiser is disclosed inWO98/11884. The use of sibutramine in lowering uric acid levels isdisclosed in WO98/13033. The use of sibutramine in lowering lipid levelsis disclosed in WO98/13034.

SUMMARY OF THE INVENTION

[0005] This invention relates to the (+)-enantiomer of Sibutramine,which isN,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine, andpharmaceutically acceptable salts thereof, to their use in the treatmentof obesity and depression, to formulations containing these compoundsand to methods for their preparation.

DETAILED DESCRIPTION OF THE INVENTION

[0006] The present invention provides a method of treating any of theindications previously disclosed as being treatable by racemicsibutramine in any of the above documents comprising administering to amammal, particularly a human, in need thereof a therapeuticallyeffective amount of (+)-sibutramine or a pharmaceutically acceptablesalt thereof, substantially free of its (−)-enantiomer.

[0007] In particular (+)-sibutramine is useful in the treatment ofdepression, obesity, Parkinson's disease, cerebral function disordersand diabetes.

[0008] The present invention provides a method of treating depression ina human which comprises administering to a human in need ofantidepressant therapy, an amount of (+)-sibutramine, or apharmaceutically acceptable salt thereof, substantially free of its(−)-stereoisomer, said amount being sufficient to alleviate depression.

[0009] In another aspect the present invention provides a method fortreating obesity or weight gain in a human which comprises administeringto a human in need of a reduction in weight, an amount of(+)-sibutramine or a pharmaceutically acceptable salt thereof,substantially free of its (−)-stereoisomer, said amount being sufficientto alleviate obesity or weight gain.

[0010] In yet another aspect the present invention provides a method oftreating disorders ameliorated by inhibition of neuronal monoaminereuptake in a human which comprises administering to a human in need ofsuch treatment an amount of (+)-sibutramine or a pharmaceuticallyacceptable salt thereof, substantially free of its (−)-stereoisomer,said amount being sufficient to alleviate said disorders. Preferablysaid monoamine is dopamine. Preferably said disorder is Parkinson'sdisease.

[0011] In yet another aspect the present invention provides a method fortreating cerebral function disorders in humans which comprisesadministering to a human an amount of (+)-sibutramine, or apharmaceutically acceptable salt thereof, substantially free of its(−)-stereoisomer, said amount being sufficient to alleviate cerebralfunction disorders. In a preferred embodiment the cerebral functiondisorder is caused by a cerebrovascular disease. In another preferredembodiment the cerebral function disorder is selected from the groupconsisting of senile dementia, Alzheimer's type dementia, memory lossand amnesia/amnestic syndrome. Preferably the cerebrovascular disease isselected from the group consisting of cerebral infarction, cerebralbleeding, cerebral arteriosclerosis, cerebral venous thrombosis and headinjuries.

[0012] The above inventions provide in preferred embodiments methods oftreating depression, obesity, weight gain, disorders ameliorated byinhibition of neuronal monoamine reuptake or cerebral function disordersin a human in which said amount of (+)-sibutramine or a pharmaceuticallyacceptable salt thereof, substantially free of its (−)-stereoisomer, issufficient to alleviate the said disease or disorder but insufficient tocause adverse effects associated with the administration of racemicsibutramine.

[0013] Examples of pharmaceutically acceptable salts of (+)-sibutramineinclude the hydrochloride, hydrobromide, sulphate, methanesulphonate,nitrate, maleate, acetate, citrate, fumarate, tartrate [e.g.(+)-tartrate, (−)-tartrate or mixtures thereof including racemicmixtures], succinate, benzoate, benzenesulphonate, camphorsulphonate,gluconate, lactate, malate, mandelate, pamoate, phosphate,p-toluenesulphonate and salts with amino acids such as glutamic acid.Preferably the salt is the hydrochloride salt.

[0014] In another aspect the present invention provides a compositionfor the treatment of depression in a human which comprises an amount of(+)-sibutramine or a pharmaceutically acceptable salt thereof,substantially free of its (−)-stereoisomer, said amount being sufficientto alleviate depression.

[0015] In a further aspect the present invention provides a compositionfor the treatment of depression in a human wherein said amount of(+)-sibutramine, or a pharmaceutically acceptable salt thereof, issufficient to treat depression but insufficient to cause adverse effectsassociated with the administration of racemic sibutramine.

[0016] In another aspect the present invention provides a compositionfor treating obesity or weight gain in a human which comprises an amountof (+)-sibutramine or a pharmaceutically acceptable salt thereof,substantially free of its (−)-stereoisomer, said amount being sufficientto alleviate obesity or weight gain.

[0017] In a further aspect the present invention provides a compositionfor treating weight disorders in a human wherein said amount issufficient to alleviate obesity or weight gain in a human butinsufficient to cause adverse effects associated with administration ofracemic sibutramine.

[0018] In another aspect the present invention provides a compositionfor the treatment of disorders ameliorated by inhibition of neuronalmonoamine reuptake in a human which comprises an amount of(+)-sibutramine or a pharmaceutically acceptable salt thereof,substantially free of its (−)-stereoisomer, said amount being sufficientto alleviate said disorders.

[0019] In a further aspect the present invention provides a compositionfor the treatment of disorders ameliorated by inhibition of neuronalmonoamine reuptake in a human wherein said amount of (+)-sibutramine ora pharmaceutically acceptable salt thereof, is sufficient to treat saiddisorders but insufficient to cause adverse effects associated with theadministration of racemic sibutramine.

[0020] In another aspect the present invention provides a compositionfor treating cerebral function disorders, which comprises an amount of(+)-sibutramine or a pharmaceutically acceptable salt thereof,substantially free of its (−)-stereoisomer, said amount being sufficientto alleviate cerebral function disorders.

[0021] In a further aspect the present invention provides a compositionfor treating cerebral function disorders wherein said amount of(+)-sibutramine or a pharmaceutically salt thereof, substantially freeof its (−)-stereoisomer, is sufficient to treat cerebral functiondisorders but insufficient to cause the adverse effects associated withthe administration of racemic sibutramine.

[0022] Preferably the above compositions comprise (+)-sibutramine and apharmaceutically acceptable diluent or carrier. In the following theterm active compound means (+)-sibutramine or a pharmaceuticallyacceptable salt thereof.

[0023] The active compound may be administered in any of the knownpharmaceutical dosage forms. The amount of the compound to beadministered will depend on a number of factors including the age of thepatient, the severity of the condition and the past medical history ofthe patient and always lies within the sound discretion of theadministering physician but it is generally envisaged that the dosage ofthe compound to be administered will be in the range from 0.1 to 100 mg,preferably 1 to about 60 mg per day, more preferably from about 2 mg toabout 50 mg per day and most preferably from about 5 mg to about 45 mgper day. Especially preferred dosages are 5 mg, 10 mg, 15 mg and 20 mgper day given in one or more doses.

[0024] Oral dosage forms are the preferred compositions for use in thepresent invention and these are the known pharmaceutical forms for suchadministration, for example tablets, capsules, granules, syrups andaqueous or oil suspensions. The excipients used in the preparation ofthese compositions are the excipients known in the pharmacist's art.Tablets may be prepared from a mixture of the active compound withfillers, for example calcium phosphate; disintegrating agents, forexample maize starch; lubricating agents, for example magnesiumstearate; binders, for example microcrystalline cellulose orpolyvinylpyrrolidone and other optional ingredients known in the art topermit tableting the mixture by known methods. The tablets may, ifdesired, be coated using known methods and excipients which may includeenteric coating using for example hydroxypropylmethylcellulosephthalate. The tablets may be formulated in a manner known to thoseskilled in the art so as to give a sustained release of the compounds ofthe present invention. Such tablets may, if desired, be provided withenteric coatings by known methods, for example by the use of celluloseacetate phthalate. Similarly, capsules, for example hard or soft gelatincapsules, containing the active compound with or without addedexcipients, may be prepared by known methods and, if desired, providedwith enteric coatings in a known manner. The contents of the capsule maybe formulated using known methods so as to give sustained release of theactive compound. The tablets and capsules may conveniently each contain0.1 to 100 mg, preferably 1 to about 60 mg per day, more preferably fromabout 2 mg to about 50 mg per day and most preferably from about 5 mg toabout 45 mg per day. Especially preferred dosages are 5 mg, 10 mg, 15 mgand 20 mg per day given in one or more doses.

[0025] Other dosage forms for oral administration include, for example,aqueous suspensions containing the active compound in an aqueous mediumin the presence of a non-toxic suspending agent such as sodiumcarboxy-methylcellulose, and oily suspensions containing a compound ofthe present invention in a suitable vegetable oil, for example arachisoil. The active compound may be formulated into granules with or withoutadditional excipients. The granules may be ingested directly by thepatient or they may be added to a suitable liquid carrier (for example,water) before ingestion. The granules may contain disintegrants, e.g. aneffervescent couple formed from an acid and a carbonate or bicarbonatesalt to facilitate dispersion in the liquid medium.

[0026] The active compound may be formulated into a composition whichthe patient retains in his mouth so that the active compound isadministered through the mucosa of the mouth.

[0027] Dosage forms suitable for rectal administration are the knownpharmaceutical forms for such administration, for example, suppositorieswith cocoa butter or polyethylene glycol bases.

[0028] Dosage forms suitable for parenteral administration are the knownpharmaceutical forms for such administration, for example sterilesuspensions or sterile solutions in a suitable solvent.

[0029] Dosage forms for topical administration may comprise a matrix inwhich the pharmacologically active compounds of the present inventionare dispersed so that the compounds are held in contact with the skin inorder to administer the compounds transdermally. A suitable transdermalcomposition may be prepared by mixing the pharmaceutically activecompound with a topical vehicle, such as a mineral oil, petrolatumand/or a wax, e.g. paraffin wax or beeswax, together with a potentialtransdermal accelerant such as dimethyl sulphoxide or propylene glycol.Alternatively the active compounds may be dispersed in apharmaceutically acceptable cream, gel or ointment base. The amount ofactive compound contained in a topical formulation should be such that atherapeutically effective amount of the compound is delivered during theperiod of time for which the topical formulation is intended to be onthe skin.

[0030] The active compound may be formulated into a composition which isdispersed as an aerosol into the patients oral or nasal cavity. Suchaerosols may be administered from a pump pack or from a pressurised packcontaining a volatile propellant.

[0031] The active compound used in the method of the present inventionmay also be administered by continuous infusion either from an externalsource, for example by intravenous infusion or from a source of thecompound placed within the body. Internal sources include implantedreservoirs containing the compound to be infused which is continuouslyreleased for example by osmosis and implants which may be (a) liquidsuch as an oily suspension of the compound to be infused for example inthe form of a very sparingly water-soluble derivative such as adodecanoate salt or a lipophilic ester or (b) solid in the form of animplanted support, for example of a synthetic resin or waxy material,for the compound to be infused. The support may be a single bodycontaining all the compound or a series of several bodies eachcontaining part of the compound to be delivered. The amount of activecompound present in an internal source should be such that atherapeutically effective amount of the compound is delivered over along period of time.

[0032] In some formulations it may be beneficial to use the compounds ofthe present invention in the form of particles of very small size, forexample as obtained by fluid energy milling.

[0033] In the compositions of the present invention the active compoundmay, if desired, be associated with other compatible pharmacologicallyactive ingredients.

[0034] The term “adverse effects” as used herein includes, but is notlimited to increases in heart rate, increases in blood pressureincluding systolic blood pressure, increased psychomotor activity, drymouth, tension and nervousness.

[0035] The term “substantially free of its (−)-stereoisomer”, as usedherein, means that the composition contains a greater proportion of the(+)-stereoisomer of sibutramine in relation to the (−)-isomer ofsibutramine. The term “substantially free of its (−)-stereoisomer”includes a composition containing an amount of the (+)-stereoisomer ofsibutramine in relation to the (−)-isomer of sibutramine such that thecomposition can perform its intended function, e.g., of treating theselected indication, e.g., treating obesity, weight gain, and/ordepression. In a preferred embodiment of the present invention the term“substantially free of its (−)-stereoisomer” as used herein means thatthe composition contains at least 90% by weight of (+)-sibutramine and10% by weight or less of (−)-sibutramine. In the most preferredembodiment, the term “substantially free of its (−)-stereoisomer” meansthat the composition contains at least 99% by weight of (+)-sibutramineand 1% or less of (−)-sibutramine. In another preferred embodiment, theterm “substantially free of its (−)-stereoisomer” as used herein meansthat the composition contains 100% by weight of the (+)-isomer ofsibutramine. The above percentages are based on the total amount ofsibutramine present in the composition. The terms “substantiallyoptically pure (+)-sibutramine”, “optically pure (+)-sibutramine” and“(+)-isomer of sibutramine” are also encompassed by the above describedamounts.

[0036] The invention is illustrated by the following Examples which aregiven by way of example only. The final product of each of theseExamples was characterised by one or more of the following procedures:gas-liquid chromatography; high performance liquid chromatography;elemental analysis, nuclear magnetic resonance spectroscopy and infraredspectroscopy.

EXEMPLIFICATION OF THE INVENTION

[0037] The (+)-enantiomer of sibutramine was obtained byN,N-dimethylation of the (+)-enantiomer of the primary amine precursorwhich was obtained by resolution of racemic1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine, which was preparedaccording to GB 2098602. (S)-(+)-N-carbamoylphenylalanine was mixed withthe racemic primary amine in methanol to give a diastereoisomericmixture of salts. One salt crystallised preferentially from the mixtureand this was recrystallised from methanol and basified to afford the(+)-primary amine which had an optical purity >98% (by nmr).Concentration of the filtrate gave the other salt which upon similartreatment gave the (−)-primary amine. The two primary amines wereN,N-dimethylated by methods described in GB 2098602 to give the tertiaryamines which were converted into their hydrochloride salts. Both the(+)-tertiary amine hydrochloride and the (−)-tertiary aminehydrochloride were at least 98% optically pure by NMR. Analytical datafor these two samples are given below.

[0038] Physicochemical Data for(+)-N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N,N-dimethylamineHydrochloride

[0039] m.p. 232° C.

[0040] [α]D=+4.5°(c=2.61; ethanol)

[0041] Optical purity: >98% by nmr

[0042] Elemental analysis:

[0043] C₁₇H₂₆CIN. HCI requires: C=64.6; H=8.5; N=4.4; CI=22.5% Found:C=65.0; H=8.6; N=4.5; CI=22.8%

[0044] The absolute stereochemistry was determined X-ray crystallographyand found to be R.

[0045] Physicochemical Data for(−)-N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N,N-dimethylamineHydrochloride

[0046] m.p. 232° C.

[0047] [α]D=−4.9°(c=3.8; ethanol)

[0048] Optical purity: >98% by NMR

[0049] Elemental analysis:

[0050] C₁₇H₂₆CIN. HCI requires: C=64.6; H=8.5; N=4.4; CI=22.5% Found:C=64.2; H=8.6; N=4; CI=22.9%

[0051] The absolute stereochemistry was determined X-ray crystallographyand found to be S.

In Vitro Tests

[0052] Materials

[0053] Animal brain tissue was obtained from adult male Sprague-Dawleyderived CD rats (150-250 g) Charles River (Margate). Human tissue wasobtained at post-mortem at St. George's Hospital (Tooting, London) fromsubjects who died suddenly from causes not involving the central nervoussystem and were without documented evidence of mental illness. Compoundswere obtained from the following sources: citalopram (Lundbeck, Valby)and mazindol, (Research Biochemicals International, Natick).

[0054] Radioisotopes and Reagents

[0055] Radioisotopes were obtained from the following suppliers:[propylene-2,3-³H]-GBR 12935 (40-60 Ci/mmol), [N-methyl-³H]-nisoxetinehydrochloride (70-87 Ci/mmol) and [phenyl-6′-³H]-paroxetine (15-30Ci/mmol), were obtained from New England Nuclear Research Products, UK.All other reagents were of analytical grade purity and were obtainedfrom Fisher (Loughborough), Sigma (Poole) or BDH (Poole).

[0056] Methods

[0057] Buffer and Compound Preparation

[0058] All buffers were prepared using distilled water. Compounds weredissolved at a concentration of 10⁻² or 10⁻³ M in distilled water.

[0059] Inhibition Constants (K_(i) Values)

[0060] The concentration of compound required to inhibit 50% of specificbinding (IC₅₀) was calculated using an iterative curve fitting program(Equilibrium Binding Data Analysis: EBDA) into which count data (dpm)were entered directly from the Liquid Scintillation Analyser. Thisprogram calculates specific binding in the absence and presence of arange of concentrations of compound and then converts the specificbinding values in the presence and absence of each concentration ofcompound into percentages of specific binding in the absence of compoundas described below.

[0061] Specific binding in the absence of compound:

A(dpm)=Total binding (dpm)−Non-specific binding (dpm).

[0062] Specific binding in the presence of compound (e.g. 10⁻¹⁰M):

B(dpm)=Binding 10⁻¹⁰M(dpm)−Non-specific binding (dpm).

[0063] Percentage specific binding in the presence of compound (e.g.10⁻¹⁰M):

% Specific binding 10⁻¹⁰M=B(dpm)/A(dpm)×100.

[0064] This is repeated for each concentration of compound tested.

[0065] The percentage specific binding at each concentration of compoundwas then plotted against the logarithmic of the concentration ofcompound. The IC₅₀ was calculated using the following formula:${\% \quad {Specific}\quad {binding}} = \frac{\left( {100 - D^{p}} \right)}{\left( {D_{p} + {I\quad C_{50}^{p}}} \right)}$

[0066] where

[0067] 100=maximum binding (ie binding in the absence of compound)

[0068] P=slope factor which is analogous to the Hill slope

[0069] D=concentration of compound (M).

[0070] The Hill slope is calculated to detect deviations from simpleone-site interactions. A Hill slope approximating to unity indicatesdisplacement from a single site, significantly less than unity indicatesdisplacement from multiple sites and significantly greater than unityindicates positive cooperativity.

[0071] The affinity constant (K_(i)) of the compound for the uptake orbinding site was then calculated using the Cheng and Prusoff equation:$K_{i} = \frac{I\quad C_{50}}{1 + {\lbrack L\rbrack/K_{d}}}$

[0072] where

[0073] [L]=the concentration of radioligand (M)

[0074] K_(d)=the affinity of the uptake or binding site for theradioligand.

[0075] The concentration of radioligand [L] nM${{The}\quad {concentration}\quad {of}\quad {{radioligand}\quad\lbrack L\rbrack}\quad n\quad M} = {\frac{{dpm}\quad \left( {{total}\quad {assay}\quad {radioligand}} \right)}{S\quad A \times \left( {2.22 \times 10^{12}} \right)} \times \frac{1}{{assay}\quad {volume}}}$

[0076] where

[0077] SA=specific activity of the radioligand (Ci/mmol).

[0078] Binding assays

[0079] The affinities of the (+)- and (−)-enantiomers of sibutramine andracemic sibutramine for monoamine reuptake sites were determined, invitro, by radioligand binding techniques. The experimental methodsemployed are summarised in Table 1. TABLE 1 A summary of the assaymethods used to determine the affinity of the (+)-and (−)-enantiomers ofsibutramine and racemic sibutramine for monoamine reuptake sites RatHuman 5-HT NA DA 5-HT NA DA Radioligand [³H]Paroxetine [³H]Nisoxetine[³H]GBR 12935 [³H]Paroxetine [³H]Nisoxetine [³H]GBR 12935 Concentration(nM)  0.03  0.6  1  0.1  2  2 NSB defined by Citalopram MazindolMazindol Citalopram Mazindol Mazindol Concentration (μM)  1  1  1  1  1 1 Species Rat Rat Rat Human Human Human Brain region Frontal cortexFrontal cortex Striatum Putamen Thalamus Putamen Tissue (mg/tube)  2  10 1  5  10  4 Incubation (min) 120 240 90 90 240 90 Incubation ° C.  22 4  4 22  0  4 Drug concentration (M) 10⁻¹⁰ -10⁻⁴ 10⁻⁹ -10⁻³ 10⁻⁹ -10⁻⁴10⁻¹⁰ -10⁻⁴ 10⁻⁹ -10⁻⁴ 10⁻⁹ -10⁻⁴

[0080] TABLE 2 Affinity of the (+)-and (−)-enantiomers of sibutramine,and racemic sibutramine for monoamine reuptake sites in rat and humanbrain Rat Human Compound 5-HT NA DA 5-HT NA DA (+)Sibutramine 2274 ± 263 3041 ± 233 1652 ± 175  369 ± 27  2535 ± 452  897 ± 125 [0.99 ± 0.03][1.02 ± 0.06] [1.74 ± 0.20] [1.24 ± 0.06] [0.97 ± 0.13] [1.29 ± 0.04](−)Sibutramine  944 ± 112 23792 ± 615 4477 ± 65 1226 ± 93 11233 ± 25192890 ± 363 [1.10 ± 0.03] [1.02 ± 0.08] [2.07 ± 0.16] [1.21 ± 0.09] [1.30± 0.04] [1.25 ± 0.05] Sibutramine 2135 ± 137   86 ± 10 3072 ± 50  298 ±65  5451 ± 1160  943 ± 64 [1.262 ± 0.05] [1.02 ± 0.02] [1.14 ± 0.04][0.85 ± 0.15] [1.34 ± 0.01] [1.15 ± 0.04]

[0081] 5-HT Reuptake Site Binding Assay in Rat Brain

[0082] a) Membrane Preparation

[0083] Adult male CD rats were killed by cervical dislocation, brainsremoved and frontal cortices (120-150 mg) immediately dissected.

[0084] Tissue was homogenised in ice-cold 0.25 M sucrose (1:30 w/v)using a Kinematic polytron (speed setting 6 for 30 seconds) andcentrifuged at 1000 g for 12 minutes. The supernatant was stored on iceand the pellet was resuspended in 0.25 M sucrose (1:20 w/v) andcentrifuged at 850 g for 10 minutes. Combined supernatants were diluted1:100 w/v with ice-cold 50 mM Tris-HCl, pH 7.5 (at 25° C.) containing120 mM sodium chloride and 5 mM potassium chloride (Tris buffer) andcentrifuged at 40,000 g for 10 minutes. The resulting pellet wasresuspended in 50 mM Tris buffer (1:100 w/v) and recentrifuged at 40,000g for 10 minutes. The final pellet was resuspended in 50 mM Tris buffer(equivalent to 2 mg wet weight of tissue/ml) and used immediately in thebinding assay. All centrifugations were carried out at 4° C.

[0085] b) Binding Assay

[0086] Membranes (1000 μl; equivalent to 2 mg wet weight of tissue/tube)were incubated with 200 μl [³H]paroxetine at a single concentration of30 pM and 200 μl of distilled water (total binding) or 200 μl of testcompound at 10 concentrations ranging from 10⁻¹⁰-10⁻⁴ M) or 200 μl ofcitalopram (1 μM; non-specific binding) for 2 h at 22° C.

[0087] Membrane bound radioactivity was recovered by filtration undervacuum through Whatman GF/C filters using a Brandel cell harvester.Filters were rapidly washed with 16 ml ice-cold 50 mM Tris buffer andradioactivity determined by liquid scintillation counting (2 ml PackardMV Gold scintillator).

[0088] 5-HT Reuptake Site Binding Assay in Human Brain

[0089] a) Membrane Preparation

[0090] Frozen putamen was homogenised in ice-cold 0.25 M sucrose (1:40w/v) using a motor driven teflon pestle (8 strokes at 120 rpm). Thehomogenate was centrifuged at 1000 g for 10 min to remove cell debrisand myelin. The supernatant was stored on ice and the pellet wasrehomogenised in 0.25 M sucrose (1:20 w/v) and centrifuged at 750 g for10 min to maximise recovery of membranes. The combined supernatants werediluted (1:100 w/v) with 50 mM Tris-HCl, pH 7.5 (at 25° C.) containing120 mM sodium chloride and 5 mM potassium chloride (Tris buffer) andcentrifuged at 35,000 g for 10 min. The resulting pellet was resuspendedin 50 mM Tris buffer (1:100 w/v) and recentrifuged at 35,000 g for 10minutes. The final pellet was resuspended in 50 mM Tris buffer(equivalent to 25 mg wet weight of tissue/ml) and used immediately inthe binding assay. All centrifugations were carried out at 4° C.

[0091] b) Binding Assay

[0092] Membranes (200 μl, equivalent to 5 mg wet weight of tissue/tube),1500 μl 50 mM Tris-HCl, pH 7.5 (at 25° C.) containing 120 mM sodiumchloride and 5 mM potassium chloride, 100 μl [³H]paroxetine at a singleconcentration of 0.1 nM and 100 μl of distilled water (total binding) or100 μl of test compound (at 10 concentrations ranging from −10⁻¹⁰-10 ⁻⁵M) or 100 μl of citalopram (1 μM; non-specific binding) were incubatedfor 90 min at 22° C.

[0093] Membrane bound radioactivity was recovered by filtration undervacuum through Whatman GF/C glass fibre filters using a Brandel cellharvester. Filters were rapidly washed with 16 ml ice-cold Tris buffer,and radioactivity determined by liquid scintillation counting.

[0094] Noradrenaline Reuptake Site Binding Assay in Rat Brain

[0095] a) Membrane preparation

[0096] Adult male CD rats were killed by cervical dislocation, brainsremoved and frontal cortices (120-150 mg) immediately dissected. Tissuewas homogenised in ice-cold 50 mM Tris-HCl, pH 7.4 (at 25° C.)containing 120 mM sodium chloride and 5 mM potassium chloride (Trisbuffer; 1:60 w/v) using a Kinematic polytron (speed setting 6 for 30seconds) and centrifuged at 40,000 g for 10 minutes. The supernatant wasdiscarded and the pellet rehomogenised in Tris buffer, 1:60 w/v, andcentrifuged at 40,000 g for 10 minutes. This step was repeated a furthertwice so that, in total, the brain tissue was homogenised andcentrifuged four times. The final pellet was resuspended in 50 mMTris-HCl, pH 7.4 containing 300 mM sodium chloride and 5 MM potassiumchloride (equivalent to 25 mg wet weight of tissue/ml) and usedimmediately in the binding assay. All centrifugations were carried outat 4° C.

[0097] b) Binding Assay

[0098] Membranes (400 μl; equivalent to 10 mg wet weight of tissue/tube)were incubated with 50 μl [³H]nisoxetine at a single concentration of0.6 nM and 50 μl of distilled water (total binding) or 50 μl of testcompound (at 10 concentrations ranging from 10⁻⁹-10⁻³ M) or 50 μl ofmazindol (1 μM; non-specific binding) for 4 h at 4° C.

[0099] Membrane bound radioactivity was recovered by filtration undervacuum through Skatron 11734 filters using a Skatron cell harvester.Filters were rapidly washed with ice-cold 50 mM Tris-HCl, pH 7.4containing 120 mM sodium chloride and 5 mM potassium chloride (washsetting 9,9,0) and radioactivity determined by liquid scintillationcounting (1 ml Packard MV Gold scintillator).

[0100] Noradrenaline Reuptake Site Binding Assay in Human Brain

[0101] a) Membrane Preparation

[0102] Frozen thalamus was homogenised in ice-cold 0.25 M sucrose (1:40w/v) using a motor driven teflon pestle (8 strokes at 120 rpm). Thehomogenate was centrifuged at 1000 g for 10 min to remove cell debrisand myelin. The supernatant was stored on ice and the pellet wasrehomogenised in 0.25 M sucrose (1:20 w/v) and centrifuged at 750 g for10 min to maximise recovery of membranes. The combined supernatants werediluted (1:100 w/v) with 50 mM Tris-HCl, pH 7.4 (at 25° C.) containing300 mM sodium chloride and 5 mM potassium chloride (Tris buffer) andcentrifuged at 35,000 g for 10 min. The pellet was resuspended in Trisbuffer (1:40 w/v) and incubated at 37° C. for 10 min (to removeendogenous neurotransmitters) and recentrifuged at 35,000 g for 10minutes. The final pellet was resuspended in 50 mM Tris buffer(equivalent to 28.6 mg wet weight of tissue/ml) and used immediately inthe binding assay. All centrifugations were carried out at 4° C.

[0103] b) Binding Assay

[0104] ,Membranes (350 μl, equivalent to 10 mg wet weight oftissue/tube), 50 μl of 50 mM Tris-HCl, pH 7.4 (at 25° C.) containing 300mM sodium chloride and 5 mM potassium chloride, 50 μl of [³H]nisoxetineat a single concentration of 2 nM and 50 μl of distilled water (totalbinding) or 100 μl of test compound (at 10 concentrations ranging from10⁻⁹-10⁻⁴ M) or 100 μl of mazindol (1 μM; non-specific binding) wereincubated for 4 h at 0° C.

[0105] Membrane bound radioactivity was recovered by filtration undervacuum through Whatman GF/C glass fibre filters using a Brandel cellharvester. Filters were rapidly washed with 16 ml ice-cold Tris buffer,and radioactivity determined by liquid scintillation counting.

[0106] Dopamine Reuptake Site Binding Assay in Rat Brain

[0107] a) Membrane preparation

[0108] Adult male CD rats were killed by cervical dislocation, brainsremoved and striata (50-80 mg) immediately dissected. Tissue washomogenised in ice-cold 0.32 M sucrose (1:80 w/v) using a motor driventeflon pestle (12 strokes, 800 rpm) and centrifuged at 1000 g for 12minutes. The supernatant was stored on ice and the pellet wasresuspended in 0.32 M sucrose (1:80 w/v) and centrifuged at 850 g for 10minutes. Combined supernatants were diluted to 1:320 w/v with ice-cold50 mM Tris-HCl, pH 7.4 (at 25° C.) containing 200 mM sodium chloride and5 mM potassium chloride and centrifuged at 40,000 g for 10 minutes. Theresulting pellet was resuspended in 10 ml of 50 mM Tris buffer,incubated at 37° C. for 10 min, diluted in 50 mM Tris buffer (1:320 w/v)and recentrifuged at 40,000 g for 10 minutes. The final pellet wasresuspended in 50 mM Tris buffer (equivalent to 1.25 mg wet weight oftissue/ml) and used immediately in the binding assay. Allcentrifugations were carried out at 4° C.

[0109] b) Binding Assay

[0110] Membranes (800 μl; equivalent to 1 mg wet weight of tissue/tube)were incubated with 100 μl [³H]GBR 12935 at a single concentration of 1nM and 100 μl of distilled water (total binding) or 100 μl of testcompound (at 10 concentrations ranging from 10⁻⁹-10⁻⁴ M) or 100 μl ofmazindol (1 μM; non-specific binding) for 90 min at 4° C.

[0111] Membrane bound radioactivity was recovered by filtration undervacuum through Whatman GF/C filters, pre-soaked for 1 h in 0.5%polyethylenimine, using a Brandel cell harvester. Filters were rapidlywashed with 16 ml of ice-cold 50 mM Tris-HCl, pH 7.4 and radioactivitydetermined by liquid scintillation counting (2 ml Packard MV Goldscintillator).

[0112] Dopamine Reuptake Site Binding Assay in Human Brain

[0113] a) Membrane preparation

[0114] Frozen putamen was homogenised in ice-cold 0.25 M sucrose (1:40w/v) using a motor driven teflon pestle (8 strokes at 120 rpm). Thehomogenate was centrifuged at 1000 g for 10 min to remove cell debrisand myelin. The supernatant was stored on ice and the pellet wasrehomogenised in 0.25 M sucrose (1:20 w/v) and centrifuged at 750 g for10 min to maximise recovery of membranes. The combined supernatants werediluted (1:100 w/v) with 50 mM Tris-HCl, pH 7.4 (at 25° C.) containing200 mM sodium chloride and 5 mM potassium chloride (Tris buffer) andcentrifuged at 35,000 g for 10 min. The membrane pellet was resuspendedin Tris buffer (1:40 w/v) and incubated at 37° C. for 10 min (to removeendogenous neurotransmitters) and recentrifuged at 35,000 g for 10minutes. The final pellet was resuspended in 50 mM Tris buffer(equivalent to 5 mg wet weight of tissue/ml) and used immediately in thebinding assay. All centrifugations were carried out at 4° C.

[0115] b) Binding Assay

[0116] Membranes (800 μl, equivalent to 4 mg wet weight of tissue/tube),100 μl of [³H]GBR 12935 at a single concentration of 2 nM and 100 μl ofdistilled water (total binding) or 100 μl of test compound (at 10concentrations ranging from 10⁻⁹-10⁻⁴ M) or 100 μl of mazindol (1 μM;non-specific binding) were mixed thoroughly and incubated for 90 min at0° C.

[0117] Membrane bound radioactivity was recovered by filtration undervacuum through Whatman GF/C glass fibre filters, pre-soaked for 1 h in0.5% polyethylenimine, using a Brandel cell harvester. Filters wererapidly washed with 16 ml ice-cold Tris buffer, and radioactivitydetermined by liquid scintillation counting.

In Vivo Tests

[0118] 1) Anti-depressant Screens

[0119] a) Porsolt Test in Mice

[0120] This test was carried out according to the procedure described inPorsolt, R. D. (1981). Behavioural despair. In: Antidepressants:Neurochemical, Behavioural and Clinical Perspectives, ed. S. J. Enna etal, pp. 121-139. New York: Raven Press.

[0121] b) Reserpine Reversal Screen

[0122] This was carried as described in U.S. Pat. No. 4,746,680 exceptthat the dose of reserpine was 10 mg/kg (i.p.).

[0123] The test compounds were dissolved in deionised water. Controlgroups of mice were treated with either deionised water or the standardantidepressant, amitriptyline (30 mg/kg p.o.).

[0124] Prevention of Reserpine-induced Ptosis in Rats

[0125] A further standard test for antidepressants but relying on theability of compounds to prevent rather than reverse reserpine-inducedeffects in rodents.

[0126] The compounds were tested as described in Prog.Neuro-Psychopharmacol. & Biol. Psychiat., 12, 575-584, Buckett et al.Rats were housed five per cage rather than six per cage and ptosis wasassessed twice during 60 sec rather than during 30 sec.

[0127] Analysis of Data

[0128] Data from the reserpine reversal screen in mice and the reserpineprevention test in rats were used to calculate ED₅₀ values for thereversal and prevention of reserpine-induced effects respectively.

[0129] Data from the Porsolt test were analysed in two ways. Data fromthe two experiments where all doses of each compound were testedconcurrently were combined and an ED₅₀ value (dose required to increasemobility by 50%) was calculated by linear regression after logtransformation of the doses. These data were combined with thoseobtained from an additional test to derive the LED₅₀, the lowesteffective dose to induce a 50% increase in the mobility of mice comparedto concurrently treated control mice, which is the standard measure ofactivity in this model.

Results

[0130] TABLE 3 Porsolt test Reserpine test Reserpine test Compound inmice in mice in rats (+/−)-Sibutramine 1.8 1.8 ˜1.5 (+)-Sibutramine 2.4˜1.0 0.7 (−)-Sibutramine 9.8 ˜30.0 59

Food Intake Studies

[0131] Materials and Methods

[0132] The effects of sibutramine and its enantiomers on the food intakeof laboratory rats were determined by measuring the amounts of foodingested over the 24 hour period following acute administration.

[0133] Animals

[0134] The study was carried out on a homogeneous group of 12 adultmale, Sprague-Dawley rats (Ico. OFA-SD IOPS caw) supplied by Iffa-Creda(L'Arbresle, France). They were of the same age and had been rearedunder identical conditions with an identical diet since birth. Only malerats were employed to avoid interference between the ovarian cycle andfeeding behaviour. The animals had not been subjected to any previousexperimentation. They weighed 200 g (1 week prior to arrival in thelaboratory) and were six weeks old. At the start of experimentation theyhad a mean weight of 433.2 g (range 412-477 g; SEM 5.5 g).

[0135] Rearing Conditions

[0136] The rats were housed individually in large cubic cages (40 cm perside), specially designed for studies on food intake. All spilled foodwas recovered, and each cage was equipped with individual lighting and anest box to favour regular feeding behaviour.

[0137] The cages were placed in a recognised animal house conforming togood laboratory practice. Room temperature, sound level, humidity andlight cycle were strictly controlled. The main environmental parameters(temperature, 24±2° C. and relative humidity, 45%) were recordedcontinuously.

[0138] Light Cycle

[0139] Since the rat is essentially a nocturnal animal, it consumes most(60-80%) of its calorie intake in the dark phase of the circadian cycle.To enable measurements to be made in normal working hours, the animalswere habituated to a reversed light cycle with eight hours darkness and16 hours light, with the onset of the dark phase at 09.00 h. Thisenabled evaluation of the time course of the effect of compounds overthe whole dark phase. The rats were habituated to the reversed lightcycle, handling and gastric intubation for a period of five weeks.

[0140] Diet

[0141] The rats had ad libitum access to tap water and normal laboratorychow (Extralabo M20, Piétrement, 77650 Longeville, France) in the formof round bars (15 mm diam, 10-25 mm long).

Compounds

[0142] Dosing

[0143] The activities of sibutramine and its (+)- and (−)-enantiomerswere evaluated using the same group of 12 rats in two series ofexperiments. Over the various experimental sessions, each group receivedthe following treatments accoding to a randomisation schedule. Series 1Series 2 racemic sibutramine: 1.0 mg/kg po (−)-enantiomer: 1.0 mg/kg poracemic sibutramine: 3.0 mg/kg po (−)-enantiomer: 10 mg/kg po(+)-enantiomer: 1.0 mg/kg po (−)-enantiomer: 30 mg/kg po (+)-enantiomer:3.0 mg/kg po placebo: vehicle (ultrapure water) po (−)-enantiomer: 1.0mg/kg po po (−)-enantiomer: 3.0 mg/kg po placebo: vehicle (ultrapurewater) po

[0144] Each rat received all of the various doses of test compound andplacebo. Each dose was tested in every experimental session.

[0145] Dosing

[0146] Compounds were dissolved in ultrapure water immediately afterdosing. All the doses were administered in a volume of 2 ml/kg. Anidentical volume of vehicle (ultrapure water) was administered asplacebo.

[0147] Route and Time of Administration

[0148] The compounds were administered via an intragastric tube(Carrieri, France).

[0149] Compounds were given between 08.00 h and 08.30 h and the animalswere allowed access to their usual diet, immediately before the start ofthe dark phase at 09.00 h.

[0150] Spacing of Experimental Sessions

[0151] A gap of three days was left between sessions for the firstseries and one week for the second series. This was believed to be longenough for adequate wash-out. However, prior to each experimentalsession, a possible residual effect was evaluated by comparing mean foodintake between treatment groups during the 24 hours before the nextexperimental session.

[0152] Between consecutive experimental sessions, the rats had adlibitum access to food and water and were left undisturbed apart fromthe weighing of food described above.

Measurements

[0153] Principal Measurement

[0154] Cumulative food intake was measured after acute administration ofthe test compounds. The measurements were made every hour over theeight-hour dark phase of the circadian cycle. A final measurement wasmade 24 hours after administration, at the end of the following diurnalcycle.

[0155] Control measurements

[0156] These consisted of an identical set of measurements of foodintake after administration of placebo under the same conditions asthose used for the test compounds.

[0157] Timing and Number of Measurements of Food Inntake

[0158] The measurements of food intake were carried out during thenocturnal, hyperphagic phase in animals with previous ad libitum accessto food. Animals were temporarily deprived of food for around 60 min atthe end of the light phase (08.00 h to 09.00 h) before each experimentalsession to enable the cages to be cleaned.

[0159] The amount of food ingested by each animal was determined byweighing the food pots after careful recovery of spillage. Themeasurements were made after access to the food for 30 and 60 min andthen each hour until the end of the dark phase at 17.00 h. A finalmeasurement was made on the following day, 24 hours after administrationof test compound or placebo. Overall, 10 measurements were made for eachrat in each experimental session.

[0160] Expression of Results and Statistical Analysis

[0161] The results were expressed as mean food intake at various timesafter each administration of test compound or placebo. The means werecompared by analysis of variance (ANOVA) for one repeated factor (animalnumber) and two fixed factors (A. treatment or dose, and B. time ofmeasurement). Individual means were compared post-hoc using theNewman-Keul's test, and results were considered significant if p<0.05.

[0162] The 50% effective dose (ED₅₀) was that of sibutramine or itsenantiomers which over a given period induced a 50% reduction in foodintake from the start of the experiment with respect to the food intakeof animals receiving placebo.

Results

[0163] The base line readings demonstrated that there were no residualeffects of the compounds at the end of the washout period.

[0164] Food Intake After Administration of Test Compounds

[0165] 50% Effective Dose (ED₅₀)

[0166] According to the procedure used in this study (food intakemeasured during dark phase following intragastric administration, 30 to60 min before access to food at the start of the dark phase) the ED₅₀values for the different compounds at the end of the dark phase wereestimated to be:

[0167] (+)-enantiomer: ˜1 mg/kg

[0168] (−)-enantiomer: >10 mg/kg

[0169] sibutramine: ˜2 mg/kg

1. A method of treating depression in a human which comprisesadministering to a human in need of antidepressant therapy, an amount of(+)-sibutramine, or a pharmaceutically acceptable salt thereof,substantially free of its (−)-stereoisomer, said amount being sufficientto alleviate depression.
 2. A method of treating depression in a humanaccording to Claim 1 in which said amount of (+)-sibutramine or apharmaceutically acceptable salt thereof, substantially free of its(−)-stereoisomer, is sufficient to alleviate depression but insufficientto cause adverse effects associated with the administration of racemicsibutramine.
 3. The method of claims 1 or 2 wherein (+)-sibutramine isadministered by intravenous infusion, transdermal delivery, or orally asa tablet or a capsule.
 4. The method of claim 3 wherein the amountadministered is from about 1 mg to about 60 mg per day.
 5. The method ofclaim 4 wherein the amount administered is from about 2 mg to about 50mg per day.
 6. The method of claim 5 wherein the amount administered isfrom about 5 mg to about 45 mg per day.
 7. The method of claim 3 whereinthe amount of (+)-sibutramine or a pharmaceutically acceptable saltthereof is greater than approximately 90% by weight of the total amountof sibutramine.
 8. The method of claim 3 wherein the (+)-sibutramine ora pharmaceutically acceptable salt thereof, substantially free of its(−)-stereoisomer, is administered together with a pharmaceuticallyacceptable carrier.
 9. The method according to claim 3 wherein(+)-sibutramine is administered as a hydrochloride salt.
 10. Acomposition for the treatment of depression in a human which comprisesan amount of (+)-sibutramine or a pharmaceutically acceptable saltthereof, substantially free of its (−)-stereoisomer, said amount beingsufficient to alleviate depression.
 11. A composition for the treatmentof depression in a human according to claim 10 wherein said amount of(+)-sibutramine, or a pharmaceutically acceptable salt thereof, issufficient to treat depression but insufficient to cause adverseeffects-associated with the administration of racemic sibutramine.
 12. Acomposition according to claim 10 or 11 wherein said amount is fromabout 1 mg to about 60 mg.
 13. A composition according to claims 10 or11 wherein (+)-sibutramine is in the form of hydrochloride salt.
 14. Acomposition according to claim 12 wherein said composition is adaptedfor oral administration.
 15. A composition according to claim 12 adaptedfor intravenous delivery.
 16. A composition according to claim 12adapted for use in a transdermal patch.
 17. The composition according toclaim 12 which comprises (+)-sibutramine or a pharmaceuticallyacceptable salt thereof, substantially free of its (−)-stereoisomer, anda pharmaceutically acceptable carrier.
 18. A method for treating obesityor weight gain in a human which comprises administering to a human inneed of a reduction in weight, an amount of (+)-sibutramine or apharmaceutically acceptable salt thereof, substantially free of its(−)-stereoisomer, said amount being sufficient to alleviate obesity orweight gain.
 19. A method for treating obesity or weight gain in a humanaccording to claim 18 wherein said amount is sufficient to alleviateobesity or weight gain but insufficient to cause the adverse effectsassociated with administration of racemic sibutramine.
 20. The method ofclaims 18 or 19 wherein (+)-sibutramine is administered by intravenousinfusion, transdermal delivery, or orally as a tablet or a capsule. 21.The method of claim 20 wherein the amount administered is from about 1mg to about 60 mg per day.
 22. The method of claim 21 wherein the amountadministered is from about 2 mg to about 50 mg per day.
 23. The methodof claim 22 wherein the amount administered is from about 5 mg to about45 mg per day.
 24. The method of claim 23 wherein the amount of(+)-sibutramine or a pharmaceutically acceptable salt thereof is greaterthan approximately 90% by weight of the total amount of sibutramine. 25.The method of claim 20 wherein the (+)-sibutramine or a pharmaceuticallyacceptable salt thereof, substantially free of its (−)-stereoisomer, isadministered together with a pharmaceutically acceptable carrier. 26.The method according to claims 18 or 19 wherein (+)-sibutramine isadministered as a hydrochloride salt.
 27. A composition for treatingobesity or weight gain in a human which comprises an amount of(+)-sibutramine or a pharmaceutically acceptable salt thereof,substantially free of its (−)-stereoisomer, said amount being sufficientto alleviate obesity or weight gain.
 28. A composition for treatingweight disorders in a human according to claim 27 wherein said amount issufficient to alleviate obesity or weight gain in a human butinsufficient to cause adverse effects associated with administration ofracemic sibutramine.
 29. A composition according to claims 27 or 28wherein the amount is about 1 mg to about 60 mg.
 30. A compositionaccording to claim 27 or wherein (+)-sibutramine is in the form ofhydrochloride salt.
 31. A composition according to claim 29 wherein saidcomposition is adapted for oral administration.
 32. A compositionaccording to claim 29 adapted for intravenous delivery.
 33. Acomposition according to claim 29 adapted for use in transdermal patch.34. The composition according to claim 29 which comprises(+)-sibutramine or a pharmaceutically acceptable salt thereof,substantially free of its (−)-stereoisomer, and a pharmaceuticallyacceptable carrier.
 35. A method of treating disorders ameliorated byinhibition of neuronal monoamine reuptake in a human which comprisesadministering to a human in need of such treatment an amount of(+)-sibutramine or a pharmaceutically acceptable salt thereof,substantially free of its (−)-stereoisomer, said amount being sufficientto alleviate said disorders.
 36. A method of treating disordersameliorated by inhibition of neuronal monoamine reuptake in a humanaccording to claim 35 in which said amount is sufficcient to alleviatesaid disorders but insufficient to cause adverse effects associated withadministration of racemic sibutramine.
 37. A method of treatingdisorders ameliorated by inhibition of neuronal monoamine reuptake in ahuman according to claims 35 or 36 wherein said monoamine is dopamine.38. A method of treating disorders ameliorated by inhibition of neuronalmonoamine reuptake in a human according to claims 35 or 36 wherein saiddisorder is Parkinson's disease.
 39. The method of claims 35 or 36wherein (+)-sibutramine is administered by intravenous infusion,transdermal delivery, or orally as a tablet or a capsule.
 40. The methodof claim 39 wherein the amount administered is from about 1 mg to about60 mg per day.
 41. The method of claim 40 wherein the amountadministered is from about 2 mg to about 50 mg per day.
 42. The methodof claim 41 wherein the amount administered is from about 5 mg to about45 mg per day.
 43. The method of claim 39 wherein the amount of(+)-sibutramine or a pharmaceutically acceptable salt thereof is greaterthan approximately 90% by weight of the total amount of sibutramine. 44.The method of claim 39 wherein (+)-sibutramine or a pharmaceuticallyacceptable salt thereof, substantially free of its (−)-stereoisomer isadministered together with a pharmaceutically acceptable carrier. 45.The method according to claim 39 wherein (+)-sibutramine is administeredas a hydrochloride salt.
 46. A composition for the treatment ofdisorders ameliorated by inhibition of neuronal monoamine reuptake in ahuman which comprises an amount of (+)-sibutramine or a pharmaceuticallyacceptable salt thereof, substantially free of its (−)-stereoisomer,said amount being sufficient to alleviate said disorders.
 47. Acomposition for the treatment of disorders ameliorated by inhibition ofneuronal monoamine reuptake in a human according to claim 46 whereinsaid amount of (+)-sibutramine or a pharmaceutically acceptable saltthereof, is sufficient to treat said disorders but insufficient to causeadverse effects associated with the administration of racemicsibutramine.
 48. A composition according to claims 46 or 47 wherein theamount is about 1 mg to about 60 mg.
 49. A composition according toclaims 46 or 47 wherein (+)-sibutramine is in the form of ahydrochloride salt.
 50. A composition according to claim 48 wherein saidcomposition is adapted for oral administration.
 51. A compositionaccording to claim 48 adapted for intravenous delivery.
 52. Acomposition according to claim 48 adapted for use in a transdermalpatch.
 53. The composition according to claim 48 which comprises(+)-sibutramine or a pharmaceutically acceptable salt thereof,substantially free of its (−)-stereoisomer, and a pharmaceuticallyacceptable carrier.
 54. A method for treating cerebral functiondisorders in humans which comprises administering to a human an amountof (+)-sibutramine, or a pharmaceutically acceptable salt thereof,substantially free of its (−)-stereoisomer, said amount being sufficientto alleviate cerebral function disorders.
 55. A method for treatingcerebral function disorders in a human according to claim 54 whereinsaid amount of (+)-sibutramine or a pharmaceutically acceptable thereof,substantially free of its (−)-stereoisomer, is sufficient to alleviatecerebral function disorders but insufficient to cause adverse effectsassociated with administration of racemic sibutramine.
 56. A method fortreating cerebral function disorders in a human according to claims 54or 55 wherein said disorder is caused by a cerebrovascular disease. 57.A method for treating cerebral function disorders in a human accordingto claims 54 or 55 wherein said cerebral function disorder is selectedfrom the group consisting of senile dementia, Alzheimer's type dementia,memory loss and amnesia/amnestic syndrome.
 58. A method for treatingcerebral function disorders in a human according to claim 56 whereinsaid cerebrovascular disease is selected from the group consisting ofcerebral infarction, cerebral bleeding, cerebral arteriosclerosis,cerebral venous thrombosis and head injuries
 59. The method of claims 54or 55 wherein (+)-sibutramine is adminstered by intravenous infusion,transdermal delivery, or orally as a tablet or a capsule.
 60. The methodof claim 59 wherein the amount administered is from about 1 mg to about60 mg per day.
 61. The method of claim 60 wherein the amountadministered is from about 2 mg to about 50 mg per day.
 62. The methodof claim 61 wherein the amount administered is from about 5 mg to about45 mg per day.
 63. The method of claim 59 wherein the amount of(+)-sibutramine or a pharmaceutically acceptable salt thereof is greaterthan approximately 90% by weight of the total amount of sibutramine. 64.The method of claim 59 wherein the (+)-sibutramine or a pharmaceuticallyacceptable salt thereof, substantially free of its (−)-stereoisomer, isadministered together with a pharmaceutically acceptable carrier. 65.The method according to claim 59 wherein (+)-sibutramine is administeredas a hydrochloride salt.
 66. A composition for treating cerebralfunction disorders, which comprises an amount of (+)-sibutramine or apharmaceutically acceptable salt thereof, substantially free of its(−)-stereoisomer, said amount being sufficient to alleviate cerebralfunction disorders.
 67. A composition for treating cerebral functiondisorders according to claim 66 wherein said amount of (+)-sibutramineor a pharmaceutically salt thereof, substantially free of its(−)-stereoisomer, is sufficient to treat cerebral function disorders butinsufficient to cause the adverse effects associated with theadministration of racemic sibutramine.
 68. A composition according toclaims 66 or 67 wherein the amount is about 1 mg to about 60 mg.
 69. Acomposition according to claims 66 or 67 wherein (+)-sibutramine is inthe form of a hydrochloride salt.
 70. A composition according to claim68 wherein said composition is adapted for oral administration.
 71. Acomposition according to claim 68 adapted for intravenous delivery. 72.A composition according to claim 68 adapted for use in a transdermalpatch.
 73. The composition according to claim 68 which comprises(+)-sibutramine or a pharmaceutically acceptable salt thereof,substantially free of its (−)-stereoisomer, and a pharmaceuticallyacceptable carrier.